title: SorLA regulates the activity of lipoprotein lipase by intracellular trafficking.
abstract: Many different tissues and cell types exhibit regulated secretion of lipoprotein lipase (LPL). However, the sorting of LPL in the trans Golgi network has not, hitherto, been understood in detail. Here, we characterize the role of SorLA (officially known as SorLA-1 or sortilin-related receptor) in the intracellular trafficking of LPL. We found that LPL bound to SorLA under neutral and acidic conditions, and in cells this binding mainly occurred in vesicular structures. SorLA expression changed the subcellular distribution of LPL so it became more concentrated in endosomes. From the endosomes, LPL was further routed to the lysosomes, which resulted in a degradation of newly synthesized LPL. Consequently, an 80% reduction of LPL activity was observed in cells that expressed SorLA. By analogy, SorLA regulated the vesicle-like localization of LPL in primary neuronal cells. Thus, LPL binds to SorLA in the biosynthetic pathway and is subsequently transported to endosomes. As a result of this SorLA mediated-transport, newly synthesized LPL can be routed into specialized vesicles and eventually sent to degradation, and its activity thereby regulated.
authors.affiliation: The MIND-Center, Department of Medical Biochemistry, University of Aarhus, Ole Worms Allé 1170, DK 8000 Aarhus C, Denmark.
authors.forename: Stine C
authors.initials: SC
authors.lastname: Klinger
authors.forename: Simon
authors.initials: S
authors.lastname: Glerup
authors.forename: Merete K
authors.initials: MK
authors.lastname: Raarup
authors.forename: Muriel C
authors.initials: MC
authors.lastname: Mari
authors.forename: Mette
authors.initials: M
authors.lastname: Nyegaard
authors.forename: Gerbrand
authors.initials: G
authors.lastname: Koster
authors.forename: Thaneas
authors.initials: T
authors.lastname: Prabakaran
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Nilsson
authors.forename: Maj M
authors.initials: MM
authors.lastname: Kjaergaard
authors.forename: Oddmund
authors.initials: O
authors.lastname: Bakke
authors.forename: Anders
authors.initials: A
authors.lastname: Nykjær
authors.forename: Gunilla
authors.initials: G
authors.lastname: Olivecrona
authors.forename: Claus Munck
authors.initials: CM
authors.lastname: Petersen
authors.forename: Morten S
authors.initials: MS
authors.lastname: Nielsen
mesh_terms: D000818:Animals; D002417:Cattle; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D042541:Intracellular Space / Q000737:chemistry / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport
chemical_list: D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; C102582:SORL1 protein, human; D008071:Lipoprotein Lipase